Methods of treating cancer with an FGFR inhibitor

ABSTRACT

This application relates to methods of treating cancer in a patient in need thereof, comprising administering a Fibroblast Growth Factor Receptors (FGFR) inhibitor to the patient.

FIELD OF THE INVENTION

This application relates to methods of treating cancer in a patient inneed thereof, comprising administering a Fibroblast Growth FactorReceptors (FGFR) inhibitor to the patient.

BACKGROUND OF THE INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005).

Aberrant activation of this pathway either through overexpression of FGFligands or FGFR or activating mutations in the FGFRs can lead to tumordevelopment, progression, and resistance to conventional cancertherapies. In human cancer, genetic alterations including geneamplification, chromosomal translocations and somatic mutations thatlead to ligand-independent receptor activation have been described.Large scale DNA sequencing of thousands of tumor samples has revealedthat components of the FGFR pathway are among the most frequentlymutated in human cancer. Many of these activating mutations areidentical to germline mutations that lead to skeletal dysplasiasyndromes. Mechanisms that lead to aberrant ligand-dependent signalingin human disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities (Reviewed in Knights and Cook Pharmacology & Therapeutics,2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore,development of inhibitors targeting FGFR may be useful in the clinicaltreatment of diseases that have elevated FGF or FGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical, colorectal,endometrial, gastric, head and neck, kidney, liver, lung, ovarian,prostate); hematopoietic malignancies (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom'sMacroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma,and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

The FGFR4-FGF19 signaling axis, specifically, has been implicated in thepathogenesis of a number of cancers including hepatocellular carcinoma(Heinzle et al., Cur. Pharm. Des. 2014, 20:2881). Ectopic expression ofFGF19 in transgenic mice was shown to lead to tumor formation in theliver and a neutralizing antibody to FGF19 was found to inhibit tumorgrowth in mice. In addition, overexpression of FGFR4 has been observedin a multiple tumor types including hepatocellular carcinoma,colorectal, breast, pancreatic, prostate, lung, and thyroid cancers.Furthermore, activating mutations in FGFR4 have been reported inrhabdomyosarcoma (Taylor et al. JCI 2009, 119:3395).

Inhibitors of FGFR are currently being developed for the treatment ofcancer. For example, pemigatinib, or3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, and other small molecule inhibitors ofFGFR are reported in e.g., U.S. Pat. No. 9,611,267, and US PublicationNos.: 2012/0165305; 2014/0045814; 2013/0338134; 2014/0171405;2014/0315902; 2016/0115164; 2016/0244448; 2016/0244449; and2016/0244450; and U.S. Provisional Application Nos. 62/667,166 and62/667,040 (corresponding to US Publication Nos.: 2019/0337948 and2020/0002338, respectively).

It has been estimated that 6.5-23% of adverse reactions from exposure tomultiple drugs results from drug-drug interactions. Each year, a numberof deaths occur as a result of patients adding concomitant prescriptionpharmaceutical products to their existing medication regimen. Thus,there needs for increased understanding of drug-drug interactions andimproved methods for administering cancer therapeutics (e.g.,pemigatinib) to individuals who are concomitantly being treated withother active agents.

SUMMARY OF THE INVENTION

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprisesadministering a therapeutically effective amount of pemigatinib to thepatient while avoiding the concomitant administration of a CYP3A4perpetrator.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) determining if the patient is receiving administration of a CYP3A4perpetrator; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the concomitant administration of the CYP3A4perpetrator.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a CYP3A4 perpetrator to the patientfor a time period of about 5 or more half-lives of the CYP3A4perpetrator; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient.

In some embodiments, the CYP3A4 perpetrator is a strong CYP3A4inhibitor. In some embodiments, the CYP3A4 perpetrator is a moderate tostrong CYP3A4 inducer.

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprises:

(a) determining if the patient is receiving administration of a strongCYP3A4 inhibitor; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the concomitant administration of a strongCYP3A4 inhibitor.

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprises:

(a) determining if the patient is receiving administration of a moderateto strong CYP3A4 inducer; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the concomitant administration of a moderateto strong CYP3A4 inducer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the plasma concentration of pemigatinib in healthyvolunteers after administration of pemigatinib with or withoutcoadministration of itraconazole.

FIG. 2 shows the plasma concentration of pemigatinib in healthyvolunteers after administration of pemigatinib with or withoutcoadministration of rifampin.

FIG. 3A shows the observed and simulated mean plasma concentration-timeprofiles for pemigatinib following a single oral dose of 4.5 mgpemigatinib tablet alone.

FIG. 3B shows the observed and simulated mean plasma concentration-timeprofiles for pemigatinib following a single oral dose of 13.5 mgpemigatinib tablet alone.

FIG. 4A shows the simulated and observed mean plasma concentration-timeprofiles of pemigatinib following a multiple oral dose of pemigatinibtablets at 6 mg in cancer patients. The solid line shows the simulatedmean. The dashed line shows the simulated 5% and 95%. The circles showthe observed data.

FIG. 4B shows the simulated and observed mean plasma concentration-timeprofiles of pemigatinib following a multiple oral dose of pemigatinibtablets at 9 mg in cancer patients. The solid line shows the simulatedmean. The dashed line shows the simulated 5% and 95%. The circles showthe observed data.

FIG. 4C shows the simulated and observed mean plasma concentration-timeprofiles of pemigatinib following a multiple oral dose of pemigatinibtablets at 13.5 mg in cancer patients. The solid line shows thesimulated mean. The dashed line shows the simulated 5% and 95%. Thecircles show the observed data.

FIG. 4D shows the simulated and observed mean plasma concentration-timeprofiles of pemigatinib following a multiple oral dose of pemigatinibtablets at 20 mg in cancer patients. The solid line shows the simulatedmean. The dashed line shows the simulated 5% and 95%. The circles showthe observed data.

FIG. 5A shows the Sensitivity analysis of pemigatinib f_(mCYP3 A4) ondrug interaction with itraconazole, at f_(mCYP3 A4)=0.25. The dashedline shows the simulated mean for pemigatinib alone; the solid lineshows the simulated mean for pemigatinib when co-administered withitraconazole; the open circle shows the observed mean for pemigatinibalone; the closed circle shows the observed mean for pemigatinib whenco-administered with itraconazole.

FIG. 5B shows the Sensitivity analysis of pemigatinib f_(mCYP3 A4) ondrug interaction with itraconazole, at f_(mCYP3 A4)=0.55. The dashedline shows the simulated mean for pemigatinib alone; the solid lineshows the simulated mean for pemigatinib when co-administered withitraconazole; the open circle shows the observed mean for pemigatinibalone; the closed circle shows the observed mean for pemigatinib whenco-administered with itraconazole.

FIG. 5C shows the Sensitivity analysis of pemigatinib f_(mCYP3 A4) ondrug interaction with itraconazole, at f_(mCYP3 A4)=0.75. The dashedline shows the simulated mean for pemigatinib alone; the solid lineshows the simulated mean for pemigatinib when co-administered withitraconazole; the open circle shows the observed mean for pemigatinibalone; the closed circle shows the observed mean for pemigatinib whenco-administered with itraconazole.

FIG. 5D shows the Sensitivity analysis of pemigatinib f_(mCYP3 A4) ondrug interaction with itraconazole, at f_(mCYP3 A4)=0.95. The dashedline shows the simulated mean for pemigatinib alone; the solid lineshows the simulated mean for pemigatinib when co-administered withitraconazole; the open circle shows the observed mean for pemigatinibalone; the closed circle shows the observed mean for pemigatinib whenco-administered with itraconazole.

FIG. 6A shows the simulated and observed plasma concentration-timeprofiles of pemigatinib following a single oral dose of 4.5 mgpemigatinib tablets alone (without itraconazole administration).

FIG. 6B shows the simulated and observed plasma concentration-timeprofiles of pemigatinib following a single oral dose of 4.5 mgpemigatinib tablets coadministered with itraconazole.

FIG. 7A shows the simulated and observed plasma concentration-timeprofiles of pemigatinib following a single oral dose of 13.5 mgpemigatinib tablets alone (without rifampin administration).

FIG. 7B shows the simulated and observed plasma concentration-timeprofiles of pemigatinib following a single oral dose of 13.5 mgpemigatinib tablets coadministered with rifampin.

FIG. 8 shows the observed and simulated pemigatinib AUC and C_(max)ratios with various CYP3A4 inhibitors and inducers.

DETAILED DESCRIPTION

The present disclosure is directed to, inter alia, methods of treatingcancer in a patient in need thereof, comprising administeringpemigatinib, which is3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, having the structure shown below:

Pemigatinib is described in U.S. Pat. No. 9,611,267, the entirety ofwhich is incorporated herein by reference. Pemigatinib is furtherdescribed in US Publication Nos.: 2019/0337948 and 2020/0002338, theentireties of which are incorporated herein by reference.

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprisesadministering a therapeutically effective amount of pemigatinib to thepatient while avoiding the concomitant administration of a CYP3A4perpetrator.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) determining if the patient is receiving administration of a CYP3A4perpetrator; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the concomitant administration of the CYP3A4perpetrator.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a CYP3A4 perpetrator to the patientfor a time period of about 5 or more half-lives of the CYP3A4perpetrator; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a CYP3A4 perpetrator to the patientfor a time period, wherein the time period is the shorter of i) about 5or more half-lives of the CYP3A4 perpetrator and ii) 14 days; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient.

In some embodiments, the CYP3A4 perpetrator is a strong CYP3A4inhibitor. In some embodiments, the CYP3A4 perpetrator is a moderate tostrong CYP3A4 inducer.

In some embodiments, provided herein is a method of treating cancercomprising administering a therapy to a patient in need thereof, whereinthe therapy comprises administering a therapeutically effective amountof pemigatinib to the patient while avoiding the concomitantadministration of a strong CYP3A4 inhibitor.

In some embodiments, provided herein is a method of treating cancercomprising administering a therapy to a patient in need thereof, whereinthe therapy comprises administering a therapeutically effective amountof pemigatinib to the patient while avoiding the concomitantadministration of itraconazole.

In some embodiments, provided herein is a method of treating cancercomprising administering a therapy to a patient in need thereof, whereinthe therapy comprises:

(a) determining if the patient is receiving administration of a strongCYP3A4 inhibitor; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the concomitant administration of a strongCYP3A4 inhibitor.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a strong CYP3A4 inhibitor to thepatient for a time period of about 5 or more half-lives of the strongCYP3A4 inhibitor; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient.

In some embodiments, the time period of discontinuing administration ofa strong CYP3A4 inhibitor to the patient is 6 or more half-lives of thestrong CYP3A4 inhibitor.

In some embodiments, the time period of discontinuing administration ofa strong CYP3A4 inhibitor to the patient is 7 or more half-lives of thestrong CYP3A4 inhibitor.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a strong CYP3A4 inhibitor to thepatient for a time period of about 5 or more half-lives of the strongCYP3A4 inhibitor; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the administration of the strong CYP3A4inhibitor during treatment.

Also provided herein is a method of treating cancer in a patient in needthereof, comprising orally administering an adjusted daily dosage amountof pemigatinib to the patient who is receiving concomitantadministration of a strong CYP3A4 inhibitor, wherein the adjusted dailydosage amount of pemigatinib is about 25% to about 75% of an intendeddaily dosage amount of pemigatinib, and wherein:

(a) the intended daily dosage amount of pemigatinib is a dosage amountsuitable for the patient if the patient is not receiving a concomitantstrong CYP3A4 inhibitor; or

(b) the intended daily dosage amount of pemigatinib is about 9 mg to13.5 mg for an adult patient.

In some embodiments, the administration of pemigatinib comprises:

-   -   (a) a continuous daily administration of an intended amount or        adjusted amount of pemigatinib to the patient in need thereof;        or

(b) a 21-day dosing cycle comprising: 14 days of daily administration ofan intended amount or adjusted amount of pemigatinib to the patient inneed thereof and 7 days without administration of pemigatinib.

In some embodiments, the adjusted daily dosage amount of pemigatinib isabout 40% to about 70% of the intended dosage amount of pemigatinib. Insome embodiments, the adjusted daily dosage amount of pemigatinib isabout 50% of the intended dosage amount of pemigatinib. In someembodiments, the adjusted daily dosage amount of pemigatinib is about60% to about 70% of the intended dosage amount of pemigatinib. In someembodiments, the adjusted daily dosage amount of pemigatinib is about25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 75%of the intended dosage amount of pemigatinib.

In some embodiments, the intended daily dosage amount of pemigatinib isthe dosage amount suitable for the patient if the patient is notreceiving administration of a strong CYP3A4 inhibitor. In someembodiments, the intended daily dosage of pemigatinib is about 9 mg toabout 13.5 mg. In some embodiments, the adjusted daily dosage amount ofpemigatinib is about 9 mg for patients on an intended dose of about 13.5mg of pemigatinib. In some embodiments, the adjusted daily dosage amountof pemigatinib is about 4.5 mg for patients on an intended dose of about9 mg of pemigatinib. In some embodiments, the adjusted daily dosageamount of pemigatinib is about 4.5 mg to about 9 mg.

In some embodiments, the concomitant administration of pemigatinib and astrong CYP3A4 inhibitor provides an altered therapeutic effect oradverse reaction profile of pemigatinib.

Also provided herein is a method of treating cancer in a patient in needthereof, wherein the method comprises orally administering atherapeutically effective amount of pemigatinib to the patient and anyone or more of the following:

(a) advising the patient that strong CYP3A4 inhibitors should be avoidedor discontinued;

(b) advising the patient that use of pemigatinib in patients beingtreated with strong CYP3A4 inhibitors is contraindicated;

(c) advising the patient that the concomitant administration ofpemigatinib and strong CYP3A4 inhibitors can alter the therapeuticeffect of pemigatinib;

(d) advising the patient that strong CYP3A4 inhibitors should be usedwith caution in patients receiving pemigatinib due to the potential forreduced pemigatinib clearance;

(e) advising the patient that the concomitant administration ofpemigatinib and strong CYP3A4 inhibitors resulted in about 2-folddecrease in pemigatinib clearance; or

(f) advising the patient that the concomitant administration ofpemigatinib and strong CYP3A4 inhibitors resulted in about 2-foldincrease in exposure to pemigatinib.

In some embodiments, the method comprises advising the patient thatstrong CYP3A4 inhibitors should be avoided or discontinued. In someembodiments, the method comprises advising the patient that use ofpemigatinib in patients being treated with strong CYP3A4 inhibitors iscontraindicated. In some embodiments, the method comprises advising thepatient that the concomitant administration of pemigatinib and strongCYP3A4 inhibitors can alter the therapeutic effect of pemigatinib. Insome embodiments, the method comprises advising the patient that theconcomitant administration of pemigatinib and strong CYP3A4 inhibitorsresulted in about 2-fold increase in exposure to pemigatinib. In someembodiments, the method comprises advising the patient that strongCYP3A4 inhibitors should be used with caution in patients receivingpemigatinib due to the potential for reduced pemigatinib clearance. Insome embodiments, the method comprises advising the patient that theconcomitant administration of pemigatinib and strong CYP3A4 inhibitorsresulted in about 2-fold decrease in pemigatinib clearance.

In some embodiments, the adjusted daily dosage amount of pemigatinib isthe amount that provides t_(1/2) values substantially the same ast_(1/2) values when pemigatinib is administered alone. In someembodiments, the targeted t_(1/2) value for a patient who is alsoreceiving concomitant administration of pemigatinib and a strong CYP3A4inhibitor is substantially the same as the t_(1/2) value if the patientis receiving administration of pemigatinib alone. In some embodiments,the t_(1/2) when 4.5 mg of pemigatinib is administered alone is about 12hours. In some embodiments, the t_(1/2) when 4.5 mg of pemigatinib isadministered alone is about 11 hours to about 13 hours. In someembodiments, the t_(1/2) when 4.5 mg of pemigatinib is administeredalone is about 10 hours to about 14 hours. In some embodiments, thet_(1/2) when 13.5 mg of pemigatinib is administered alone is about 13hours. In some embodiments, the t_(1/2) when 13.5 mg of pemigatinib isadministered alone is about 12 hour to about 14 hours. In someembodiments, the t_(1/2) when 13.5 mg of pemigatinib is administeredalone is about 11 hours to about 15 hours. In some embodiments, thet_(1/2) when 13.5 mg of pemigatinib is administered alone is about 10hours to about 16 hours.

In some embodiments, the adjusted daily dosage amount of pemigatinib isthe amount that provides C_(max) values substantially the same asC_(max) values when pemigatinib is administered alone. In someembodiments, the targeted C_(max) value for a patient who is alsoreceiving concomitant administration of pemigatinib and a strong CYP3A4inhibitor is substantially the same as the C_(max) value if the patientis receiving administration of pemigatinib alone. In some embodiments,the C_(max) when 4.5 mg of pemigatinib is administered alone is about 40nM to about 80 nM. In some embodiments, the C_(max) when 4.5 mg ofpemigatinib is administered alone is about 50 nM to about 70 nM. In someembodiments, the C_(max) when 4.5 mg of pemigatinib is administeredalone is about 55 nM to about 65 nM. In some embodiments, the C_(max)when 4.5 mg of pemigatinib is administered alone is about 60 nM. In someembodiments, the C_(max) when 4.5 mg of pemigatinib is administeredalone is from about 20 to about 120 nM.

In some embodiments, the C_(max) when 9 mg of pemigatinib isadministered alone is from about 50 to about 450 nM.

In some embodiments, the C_(max) when 13.5 mg of pemigatinib isadministered alone is about 190 nM to about 210 nM. In some embodiments,the C_(max) when 13.5 mg of pemigatinib is administered alone is about195 nM to about 205 nM. In some embodiments, the C_(max) when 13.5 mg ofpemigatinib is administered alone is about 200 nM. In some embodiments,the C_(max) when 13.5 mg of pemigatinib is administered alone is about90 nM to about 300 nM. In some embodiments, the C_(max) when 13.5 mg ofpemigatinib is administered alone is about 70 nM to about 700 nM.

In some embodiments, the adjusted daily dosage amount of pemigatinib isthe amount that provides AUC_(0-∞) values substantially the same asAUC_(0-∞) values when pemigatinib is administered alone. In someembodiments, the targeted AUC_(0-∞) value for a patient who is alsoreceiving concomitant administration of pemigatinib and a strong CYP3A4inhibitor is substantially the same as the AUC_(0-∞) value if thepatient is receiving administration of pemigatinib alone. In someembodiments, the AUC_(0-∞) when 4.5 mg of pemigatinib is administeredalone is about 500 nM·h to about 900 nM·h. In some embodiments, theAUC_(0-∞) when 4.5 mg of pemigatinib is administered alone is about 600nM·h to about 800 nM·h. In some embodiments, the AUC_(0-∞) when 4.5 mgof pemigatinib is administered alone is about 650 nM·h to about 750nM·h. In some embodiments, the AUC_(0-∞) when 4.5 mg of pemigatinib isadministered alone is about 700 nM·h. In some embodiments, the AUC_(0-∞)when 4.5 mg of pemigatinib is administered alone is about 430 nM·h toabout 1180 nM·h. In some embodiments, the AUC_(0-∞) when 4.5 mg ofpemigatinib is administered alone is about 1100 nM·h to about 1300 nM h.

In some embodiments, the AUC_(0-∞) when 9 mg of pemigatinib isadministered alone is about 250 nM·h to about 7000 nM·h.

In some embodiments, the AUC_(0-∞) when 13.5 mg of pemigatinib isadministered alone is about 1700 nM·h to about 2100 nM·h. In someembodiments, the AUC_(0-∞) when 13.5 mg of pemigatinib is administeredalone is about 1800 nM·h to about 2000 nM·h. In some embodiments, theAUC_(0-∞) when 13.5 mg of pemigatinib is administered alone is about1850 nM·h to about 1950 nM·h. In some embodiments, the AUC_(0-∞) when13.5 mg of pemigatinib is administered alone is about 1900 nM·h. In someembodiments, the AUC_(0-∞) when 13.5 mg of pemigatinib is administeredalone is about 900 nM·h to about 13000 nM·h.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises the concomitant administering of a therapeuticallyeffective amount of pemigatinib and a mild to moderate CYP3A4 inhibitor,and wherein the concomitant administration provides substantially thesame therapeutic effect or adverse reaction profile of pemigatinibcompared to when pemigatinib is administered alone.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises the concomitant administering of a therapeuticallyeffective amount of pemigatinib and a mild to moderate CYP3A4 inhibitor,wherein the concomitant administering demonstrated no significantpharmacokinetic interaction.

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprisesadministering a therapeutically effective amount of pemigatinib to thepatient while avoiding the concomitant administration of a moderate tostrong CYP3A4 inducer.

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprisesadministering a therapeutically effective amount of pemigatinib to thepatient while avoiding the concomitant administration of rifampin.

Provided herein is a method of treating cancer comprising administeringa therapy to a patient in need thereof, wherein the therapy comprises:

(a) determining if the patient is receiving administration of a moderateto strong CYP3A4 inducer; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the concomitant administration of a moderateto strong CYP3A4 inducer.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a moderate to strong CYP3A4 inducerto the patient for a time period of about 5 or more half-lives of themoderate to strong CYP3A4 inducer; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient.

In some embodiments, the time period of discontinuing administration ofa moderate to strong CYP3A4 inducer to the patient is 6 or morehalf-lives of the moderate to strong CYP3A4 inducer. In someembodiments, the time period of discontinuing administration of amoderate to strong CYP3A4 inducer to the patient is 7 or more half-livesof the moderate to strong CYP3A4 inducer.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises:

(a) discontinuing administration of a moderate to strong CYP3A4 inducerto the patient for a time period of about 5 or more half-lives of themoderate to strong CYP3A4 inducer; and

(b) administering a therapeutically effective amount of pemigatinib tothe patient while avoiding the administration of the moderate to strongCYP3A4 inducer during treatment.

In some embodiments, the total daily amount of pemigatinib is about 9 mgto about 13.5 mg.

In some embodiments, the concomitant administration of pemigatinib and amoderate to strong CYP3A4 inducer provides an altered therapeutic effectof pemigatinib.

Also provided herein is a method of treating cancer in a patient in needthereof, wherein the method comprises orally administering atherapeutically effective amount of pemigatinib to the patient and anyone or more of the following:

(a) advising the patient that moderate to strong CYP3A4 inducers shouldbe avoided or discontinued;

(b) advising the patient that use of pemigatinib in patients beingtreated with moderate to strong CYP3A4 inducers is contraindicated;

(c) advising the patient that the concomitant administration ofpemigatinib and moderate to strong CYP3A4 inducers can alter thetherapeutic effect of pemigatinib;

(d) advising the patient that moderate to strong CYP3A4 inducers shouldbe used with caution in patients receiving pemigatinib due to thepotential for increased pemigatinib clearance;

(e) advising the patient that the concomitant administration ofpemigatinib and strong CYP3A4 inducers resulted in about 6-fold to about7-fold increase in pemigatinib clearance; or

(f) advising the patient that the concomitant administration ofpemigatinib and moderate to strong CYP3A4 inducers resulted in about6-fold to about 7-fold decrease in exposure to pemigatinib.

In some embodiments, the method further comprises advising the patientthat moderate to strong CYP3A4 inducers should be avoided ordiscontinued. In some embodiments, the method comprises advising thepatient that use of pemigatinib in patients being treated with moderateto strong CYP3A4 inducers is contraindicated. In some embodiments, themethod comprises advising the patient that the concomitantadministration of pemigatinib and moderate to strong CYP3A4 inducers canalter the therapeutic effect of pemigatinib. In some embodiments, themethod comprises advising the patient that moderate to strong CYP3A4inducers should be used with caution in patients receiving pemigatinibdue to the potential for increased pemigatinib clearance. In someembodiments, the method comprises advising the patient that theconcomitant administration of pemigatinib and strong CYP3A4 inducersresulted in about 6-fold to about 7-fold increase in pemigatinibclearance. In some embodiments, the method comprises advising thepatient that the concomitant administration of pemigatinib and moderateto strong CYP3A4 inducers resulted in about 6-fold to about 7-folddecrease in exposure to pemigatinib. In some embodiments, the methodcomprises advising the patient that the concomitant administration ofpemigatinib and moderate to strong CYP3A4 inducers resulted in about2-fold decrease in exposure to pemigatinib. In some embodiments, themethod comprises advising the patient that the concomitantadministration of pemigatinib and moderate to strong CYP3A4 inducersresulted in about 7-fold decrease in exposure to pemigatinib.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises the concomitant administering a therapeuticallyeffective amount of pemigatinib and a mild CYP3A4 inducer, and whereinthe concomitant administration provides substantially the sametherapeutic effect or adverse reaction profile of pemigatinib comparedto when pemigatinib is administered alone.

Also provided herein is a method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises the concomitant administering of a therapeuticallyeffective amount of pemigatinib and a mild CYP3A4 inducer, wherein theconcomitant administering demonstrated no significant pharmacokineticinteraction.

Also provided herein is a method of increasing the effectiveness ofpemigatinib therapy by avoiding decreased exposure to pemigatinib, in apatient in need of pemigatinib therapy that is receiving a moderate tostrong CYP3A4 inducer comprising discontinuing the moderate to strongCYP3A4 inducer to decrease the levels of CYP3A4 induction, and thenadministering a therapeutically effective amount of pemigatinib.

In some embodiments, the time period of discontinuing administration ofa moderate to strong CYP3A4 inducer is 5 or more half-lives of themoderate to strong CYP3A4 inducer. In some embodiments, the time periodof discontinuing administration of a moderate to strong CYP3A4 induceris 6 or more half-lives of the moderate to strong CYP3A4 inducer. Insome embodiments, the time period of discontinuing administration of amoderate to strong CYP3A4 inducer is 7 or more half-lives of themoderate to strong CYP3A4 inducer. In some embodiments, the time periodof discontinuing administration of a moderate to strong CYP3A4 induceris two to three weeks prior to pemigatinib administration.

Also provided herein is a method of treating a patient with pemigatinibwherein the patient is coadministering a substance that is a knownstrong inhibitor of CYP3A4, said method comprising adjustingadministration to the patient of the substance to avoid an adverse eventassociated with a change in the metabolism of pemigatinib.

Also provided herein is a method of treating a patient with pemigatinibwherein the patient is coadministering a substance that is a knownstrong inhibitor or a known moderate to strong inducer of CYP3A4, saidmethod comprising adjusting administration of pemigatinib or thesubstance to the patient to avoid an adverse reaction or asubtherapeutic outcome with pemigatinib.

In some embodiments, the adjusting administration of pemigatinib is adosage amount suitable for the patient if the patient is not receiving aconcomitant strong CYP3A4 inhibitor. In some embodiments, the adjustingadministration of the substance is avoiding the coadministration of thesubstance that is a known moderate to strong inducer of CYP3A4.

Also provided herein is a method of avoiding an adverse event whenadministering pemigatinib, comprising determining that a patient in needof pemigatinib therapy is taking a substance that is a known stronginhibitor or a known moderate to strong inducer of CYP3A4; and adjustingadministration to the patient of pemigatinib or the substance to avoidan adverse event associated with a change in the metabolism ofpemigatinib, wherein the adjusting administration comprises ceasing toadminister the substance if the substance is a moderate to stronginducer of CYP3A4 or decreasing the dosage of pemigatinib if thesubstance is a strong inhibitor of CYP3A4.

Also provided herein is a method of avoiding an adverse event whenadministering pemigatinib, comprising avoiding coadministration ofpemigatinib with moderate to strong CYP3A4 inducers or strong CYP3A4inhibitors.

Also provided herein is a method of avoiding an adverse event whenadministering pemigatinib, comprising avoiding concomitantadministration of pemigatinib with moderate to strong CYP3A4 inducers orstrong CYP3A4 inhibitors.

Also provided herein is a method of avoiding an adverse event whenadministering pemigatinib, comprising avoiding concomitant use ofpemigatinib with moderate to strong CYP3A4 inducers or strong CYP3A4inhibitors.

Exemplary CYP3A inhibitors (e.g., strong CYP3A4 inhibitors, moderateCYP3A4 inhibitors, and mild CYP3A4 inhibitors) are shown below in thefollowing table.

TABLE 1 CYP3A Inhibitors Inhibitor Therapeutic Class Strong CYP3AInhibitors VIEKIRA PAK Antivirals Indinavir/RIT Protease inhibitorsTipranavir/RIT Protease inhibitors Ritonavir Protease inhibitorsKetoconazole Antifungals Indinavir Protease inhibitors TroleandomycinAntibiotics Telaprevir Antivirals Danoprevir/RIT AntiviralsElvitegravir/RIT Treatments of AIDS Saquinavir/RIT Protease inhibitorsLopinavir/RIT Protease inhibitors Itraconazole Antifungals VoriconazoleAntifungals Mibefradil Calcium channel blockers ClarithromycinAntibiotics Posaconazole Antifungals Telithromycin AntibioticsGrapefruit juice DS Food products Conivaptan Diuretics NefazodoneAntidepressants Nelfinavir Protease inhibitors Saquinavir Proteaseinhibitors Ribociclib Kinase inhibitors Idelalisib Kinase inhibitorsBoceprevir Antivirals Moderate CYP3A Inhibitors Erythromycin AntibioticsFluconazole Antifungals Atazanavir/RIT Protease inhibitors DarunavirProtease inhibitors Diltiazem Calcium channel blockers Darunavir/RITProtease inhibitors Dronedarone Antiarrhythmics Crizotinib Kinaseinhibitors Atazanavir Protease inhibitors Letermovir AntiviralsAprepitant Antiemetics Casopitant Antiemetics Amprenavir Proteaseinhibitors Faldaprevir Antivirals Imatinib Antineoplastic agentsVerapamil Calcium channel blockers Netupitant Antiemetics NilotinibKinase inhibitors Grapefruit juice Food products TofisopamBenzodiazepines Cyclosporine Immunosuppressants ACT-178882 Renininhibitors Ciprofloxacin Antibiotics Magnolia vine Herbal medications(Schisandra sphenanthera) Isavuconazole Antifungals Cimetidine H-2receptor antagonists Mild CYP3A Inhibitors Tabimorelin Hormonereplacement Amlodipine Calcium channel blockers RanolazineCardiovascular drugs Breviscapine Herbal medications Lomitapide Otherantilipemics Fosaprepitant (IV) Antiemetics Seville orange Food (Citrusaurantium) juice products Amiodarone Antiarrhythmics Diosmin Herbalmedications Chlorzoxazone Muscle relaxants Fluvoxamine AntidepressantsRanitidine H-2 receptor antagonists Goldenseal Herbal medicationsClotrimazole Antifungals Tacrolimus Immunosuppressants PalbociclibKinase inhibitors Cilostazol Antiplatelets Ticagrelor AntiplateletsPeppermint oil Food products Ivacaftor Cystic fibrosis treatments GuanMai Ning Herbal medications Osilodrostat Adrenal steroidogenesisinhibitors Piperine Food products Resveratrol Food productsRoxithromycin Antibiotics Suvorexant Hypnotics - sedatives PropiverineAnticholinergics Isoniazid Antibiotics Berberine Herbal medications Oralcontraceptives Oral contraceptives Delavirdine NNRTIs DaclatasvirAntivirals Simeprevir Protease inhibitors Atorvastatin HMG CoA reductaseinhibitors (statins) Tolvaptan Vasopressin antagonists AlmorexantHypnotics - sedatives Evacetrapid CETP inhibitors Linagliptin Dipeptidylpeptidase 4 inhibitors Grazoprevir Antivirals (ingredient of Zepatier)Lacidipine Calcium channel blockers Cranberry juice Food productsPazopanib Kinase inhibitors Fostamatinib Other EverolimusImmunosuppressants Blueberry juice Food products Flibanserin Centralnervous system agents Lapatinib Kinase Inhibitors BrodalumabImmunomodulators biologics Alprazolam Benzodiazepines Tong Xin LuoHerbal medications Glecaprevir and pibrentasvir Antivirals BicalutamideAntiandrogens Sitaxentan Endothelin receptor antagonists AzithromycinAntibiotics Obeticholic acid Miscellaneous agents Ginkgo Herbalmedications Teriflunomide Other immunomodulators

In some embodiments, the strong CYP3A4 inhibitor is itraconazole,ketoconazole or clarithromycin. In some embodiments, the strong CYP3A4inhibitor is itraconazole. In some embodiments, the moderate CYP3A4inhibitor is erythromycin or diltiazem. In some embodiments, the mildCYP3A4 inhibitor is fluvoxamine. In some embodiments, the CYP3A4inhibitor is erythromycin, diltiazem, or fluvoxamine.

Exemplary CYP3A inducers (e.g., strong CYP3A4 inducers, moderate CYP3A4inducers, and mild CYP3A4 inducers) are shown below in the followingtable.

TABLE 2 Inducers Therapeutic class Strong CYP3A Inducers RifampinAntibiotics Mitotane Other Antineoplastics Avasimibe Other AntilipemicsRifapentine Antibiotics Apalutamide Antiandrogens PhenytoinAnticonvulsants Carbamazepine Anticonvulsants Enzalutamide AntiandrogensSt John's Wort extract Herbal medications Lumacaftor Cystic fibrosistreatments Rifabutin Antibiotics Phenobarbital Anticonvulsants ModerateCYP3A Inducers Ritonavir and St. Johns wort None SemagacestatAlzheimer's treatments Efavirenz NNRTIs Tipranavir and ritonavirProtease inhibitors Dabrafenib Kinase inhibitors Lesinurad Antigout anduricosuric agents Bosentan Endothelin receptor antagonists GenisteinFood products Thioridazine Antipsychotics Nafcillin AntibioticsTalviraline NNRTIs Lopinavir Protease inhibitors ModafinilPsychostimulants Etravirine NNRTIs Lersivirine NNRTIs Telotristat ethylAntidiarrheals Mild CYP3A Inducers Eslicarbazepine AnticonvulsantsTelaprevir Antivirals Daclatasvir and Antivirals asunaprevir andbeclabuvir Amenamevir Antivirals Garlic Food products Bexarotene Otherantineoplastics Sarilumab Immunomodulators biologics Artesunate andmefloquine Antimalarials Amprenavir Protease (fosamprenavir) inhibitorsRaltegravir HIV-integrase strand transfer inhibitors Vemurafenib Kinaseinhibitors Troglitazone Thiazolidinediones Dicloxacillin AntibioticsSorafenib Kinase inhibitors Rufinamide Anticonvulsants SirukumabImmunomodulators biologics Pleconaril Antivirals Ginseng Herbalmedications Boceprevir Antivirals Sulfinpyrazone Antigout and uricosuricagents Ginkgo Herbal medications Vinblastine Vinca alkaloids NevirapineNNRTIs Armodafmil (R-modafmil) Psychostimulants TicagrelorAnticoagulants and antiplatelets Vicriviroc and ritonavir Treatments ofAIDS Ritonavir Protease inhibitors Prednisone CorticosteroidsOxcarbazepine Anticonvulsants Danshen Herbal medications ClobazamBenzodiazepines Echinacea Herbal medications Ticlopidine Anticoagulantsand antiplatelets Isavuconazole Antifungals Brivaracetam AnticonvulsantsStribild Treatments of AIDS Pioglitazone Thiazolidinediones VIEKIRA PAKAntivirals Dexamethasone Corticosteroids Terbinafine AntifungalsQuercetin Food products Glycyrrhizin Herbal medications AprepitantNeurokinin-1 receptor antagonists Pretomanib (PA-824) AntibioticsSafinamide MAO-B inhibitors Oritavancin Antibiotics MethylprednisoloneCorticosteroids Topiramate Anticonvulsants

In some embodiments, the strong CYP3A4 inducer is rifampin. In someembodiments, the moderate CYP3A4 inducer is efavirenz. In someembodiments, the mild CYP3A4 inducer is dexamethasone. In someembodiments, the CYP3A4 inducer is rifampin or efavirenz.

Pemigatinib as described herein can inhibit the activity of the FGFRenzyme. For example, pemigatinib can be used to inhibit activity of anFGFR enzyme in a cell or in an individual or patient in need ofinhibition of the enzyme by administering an inhibiting amount ofpemigatinib to the cell, individual, or patient.

As an FGFR inhibitor, pemigatinib is useful in the treatment of variousdiseases associated with abnormal expression or activity of the FGFRenzyme or FGFR ligands. Compounds which inhibit FGFR will be useful inproviding a means of preventing the growth or inducing apoptosis intumors, particularly by inhibiting angiogenesis. It is thereforeanticipated that pemigatinib will prove useful in treating or preventingproliferative disorders such as cancers. In particular tumors withactivating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors.

In certain embodiments, the disclosure provides a method for treating aFGFR-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient pemigatinib, or a pharmaceuticallyacceptable composition thereof.

For example, pemigatinib is useful in the treatment of cancer. Examplecancers include bladder cancer, breast cancer (e.g., hormone R positive,triple negative), cervical cancer, colorectal cancer, cancer of thesmall intestine, colon cancer, rectal cancer, cancer of the anus,endometrial cancer, gastric cancer (e.g., gastrointestinal stromaltumors), head and neck cancer (e.g., cancers of the larynx, hypopharynx,nasopharynx, oropharynx, lips, and mouth, squamous head and neckcancers), kidney cancer (e.g., renal cell carcinoma, urothelialcarcinoma, sarcoma, Wilms tumor), liver cancer (e.g., hepatocellularcarcinoma, cholangiocellular carcinoma, liver angiosarcoma,hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lungcancer and non-small cell lung carcinomas, parvicellular andnon-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma,pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicularcancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladdercancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma), stomachcancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g.,pheochromocytoma, Merkel cell cancer, neuroendocrine carcinoma), skincancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skincancer), and brain cancer (e.g., astrocytoma, medulloblastoma,ependymoma, neuro-ectodermal tumors, pineal tumors).

Further example cancers include hematopoietic malignancies such asleukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma,adult T cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acutemyelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma,myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome,polycythemia vera, essential thrombocythemia, and primarymyelofibrosis), myelodysplastic syndrome, chronic eosinophilic leukemia,Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogeniclymphoma, acute lymphoblastic lymphoma, AIDS-related lymphomas, andBurkitt's lymphoma.

In certain embodiments, provided herein is a method of treatingmyeloid/lymphoid neoplasms in a patient in need thereof. In certainembodiments, the myeloid/lymphoid neoplasms are 8p11 myeloproliferativesyndrome. As used herein, the term “8p11 myeloproliferative syndrome”(EMS) is meant to refer to myeloid/lymphoid neoplasms associated witheosinophilia and abnormalities of FGFR1 or myeloid/lymphoid neoplasms(MLN) with FGFR1 rearrangement. Eight P eleven myeloproliferativesyndrome is reviewed in Jackson, Courtney C., et. al. Human Pathology,2010, 41, 461-476. In certain embodiments, the myeloid/lymphoid neoplasmexhibits an 8p11 translocation. In certain embodiments, the 8p11translocation is associated with activation of FGFR1. In certainembodiments, the patient has failed at least one previous treatment formyeloid/lymphoid neoplasms (e.g., 8p11 myeloproliferative syndrome). Insome embodiments, the previous treatment is surgery or radiationtherapy. In some embodiments, the patient has a history of hepatitis. Insome embodiments, the hepatitis is chronic hepatitis B or hepatitis C.In some embodiments, the patient does not have a history of hepatitis.

In certain embodiments, provided herein is a method of treating cancercomprising administering to a patient in need thereof a therapeuticallyeffect amount of pemigatinib. In certain embodiments, the cancer isselected from bladder cancer, breast cancer, cervical cancer, cancer ofthe small intestine, colorectal cancer, endometrial cancer, gastriccancer, head and neck cancer, kidney cancer, liver cancer, lung cancer,ovarian cancer, prostate cancer, testicular cancer, uterine cancer,vulvar cancer, esophageal cancer, gall bladder cancer, pancreaticcancer, thyroid cancer, skin cancer, brain cancer, leukemia, multiplemyeloma, chronic lymphocytic lymphoma, adult T cell leukemia, B-celllymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin'slymphoma, Waldenstrom's Macroglubulinemia, myeloproliferative neoplasms,chronic myelogenic lymphoma, acute lymphoblastic lymphoma, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, rhabdosarcoma,lymphosarcoma, and osteosarcoma.

In certain embodiments, the cancer is bladder cancer (e.g., urothelialcarcinoma, squamous cell carcinoma, adenocarcinoma).

In certain embodiments, the liver cancer is cholangiocellular carcinoma(e.g., intrahepatic, hilar or perihilar, distal extrahepatic). As usedherein, cholangiocellular carcinoma is the same as cholangiocarcinoma orbile duct cancer. In certain embodiments, the cholangiocarcinoma isadvanced or metastatic cholangiocarcinoma. In certain embodiments, thecholangiocarcinoma is surgically unresectable. In certain embodiments,the cholangiocarcinoma is intrahepatic. In certain embodiments, thecholangiocarcinoma is extrahepatic. In certain embodiments, thecholangiocarcinoma exhibits FGFR2 tyrosine kinase fusions which define aunique molecular subtype as described in Arai, Yasuhito, et. al.Hepatology, 2014, 59, 1427-1434. In some embodiments, thecholangiocarcinoma is characterized by FGF/FGFR genetically alteredtumors. In some embodiments, the tumors exhibit FGFR2 fusions. The FGFR2fusion can be a translocation, interstitial deletion, or a chromosomalinversion. In some embodiments, the FGFR2 fusion is an FGFR2translocation. The FGFR2 translocations can be selected from a groupincluding, but not limited to, FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1,FGFR2 intron 17 rearrangement. In some embodiments, the tumor exhibitsFGF/FGFR alterations other than FGFR2 translocations. In someembodiments, the cholangiocarcinoma does not exhibit FGF/FGFRgenetically altered tumors.

Other cancers treatable with the methods provided herein include tumorsof the eye, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma,leiomyosarcoma, urothelial carcinoma (e.g., ureter, urethra, bladder,urachus), and osteosarcoma.

Pemigatinib can also be useful in the inhibition of tumor metastases.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; for example, inhibiting a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., arresting further development of the pathology and/orsymptomatology); and (2) ameliorating the disease; for example,ameliorating a disease, condition or disorder in an individual who isexperiencing or displaying the pathology or symptomatology of thedisease, condition or disorder (i.e., reversing the pathology and/orsymptomatology) such as decreasing the severity of disease. In someembodiments, the term “treating” or “treatment” refers to inhibiting orameliorating the disease.

As used herein, the term “coadministering” or “concomitantadministering” refers to administering pemigatinib and one or moreadditional drugs (e.g., a CYP3A4 perpetrator) at or almost at the sametime. For example, pemigatinib may be administered, e.g., on the sameday, within a week, or within a month as the one or more additionaldrugs. In some embodiments, the one or more additional drugs isadministered between administrations of pemigatinib.

As used herein, the term “therapy” refers to administration of acompound that is suitable for treating cancer. For example, therapy canrefer to the administration of pemigatinib for treating cancer.

As used herein, the term “perpetrator” refers to a drug or compound thatcauses an effect on the substrate drug by inhibiting or inducing enzymesor transporters (e.g., CYP3A4). In some embodiments, the substrate drugis pemigatinib. A perpetrator can refer to, e.g., a CYP3A4 inhibitor ora CYP3A4 inducer.

As used herein, the term “C_(max)” refers to the maximum (or peak) serumconcentration that a drug (e.g., pemigatinib) achieves in a specifiedcompartment or test area of the body after the drug has beenadministered and before the administration of a second dose.

As used herein, the term “AUC” refers to the definite integral in a plotof drug (e.g., pemigatinib) concentration in blood plasma vs. time. Theterm “AUC_(0-∞).” refers to the area under the concentration vs. timecurve extrapolated to infinity. The term “AUC_(0-t)” refers to the areaunder the concentration vs. time curve up to the last measurableconcentration.

As used herein, the term “t_(1/2)” refers to the time it takes for theserum concentration of a drug (e.g., pemigatinib) to fall to half of itsoriginal value. In other words, t_(1/2) refers to the biologicalhalf-life of a drug (e.g., pemigatinib).

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values, indicatethat the value or range of values may deviate to an extent deemedreasonable by one of ordinary skill in the art. Specifically, the term“about”, when used in this context, indicates that the numeric value orrange of values may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%,0.5%, 0.4%, 0.3%, 0.2% or 0.1% of the recited value or range of values.

As used herein, and unless otherwise specified, the term “substantial”or “substantially the same,” when used in connection with a numericvalue or range of values, indicate that the value or range of values maydeviate to an extended deemed reasonable by one of ordinary skill in theart. Specifically, the term “substantially the same,” when used in thiscontext, indicates that the numeric value or range of values may vary by20%, 10%, 15%, 5%, or 1% of the recited value or range of values. Insome embodiments, the phrase “substantially the same” indicates that thenumeric value or range of values may vary by 10%.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with pemigatinib includes theadministration of a compound described herein to an individual orpatient, such as a human, having FGFR, as well as, for example,introducing pemigatinib into a sample containing a cellular or purifiedpreparation containing the FGFR enzyme.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

In some embodiments, a pharmaceutically acceptable salt of pemigatinibis used in the methods and combination therapies described herein. Saltforms of pemigatinib are described in U.S. Provisional Application No.62/667,040.

Solid forms (e.g., crystalline forms) of pemigatinib can also be used inthe methods and combination therapies described herein. Solid forms ofpemigatinib, and methods of preparing solid forms of pemigatinib, aredescribed in U.S. Provisional Application No. 62/667,166.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withpemigatinib for treatment of FGFR-associated diseases, disorders orconditions, or diseases or conditions as described herein. The agentscan be combined with the present compounds in a single dosage form, orthe agents can be administered simultaneously or sequentially asseparate dosage forms.

Pemigatinib can be used in combination with one or more other kinaseinhibitors for the treatment of diseases, such as cancer, that areimpacted by multiple signaling pathways. For example, a combination caninclude one or more inhibitors of the following kinases for thetreatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2,HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II,KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea,TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2,EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK andB-Raf Additionally, pemigatinib can be combined with inhibitors ofkinases associated with the PIK3/Akt/mTOR signaling pathway, such asPI3K, Akt (including Akt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, pemigatinib can be used in combination with one ormore inhibitors of the enzyme or protein receptors such as HPK1, SBLB,TUT4, A2A/A2B, CD47, CDK2, STING, ALK2, LIN28, ADAR1, MAT2a, RIOK1,HDAC8, WDR5, SMARCA2, and DCLK1 for the treatment of diseases anddisorders. Exemplary diseases and disorders include cancer, infection,inflammation and neurodegenerative disorders.

In some embodiments, pemigatinib can be used in combination with atherapeutic agent that targets an epigenetic regulator. Examples ofepigenetic regulators include bromodomain inhibitors, the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, pemigatinib can beused in combination with targeted therapies, including JAK kinaseinhibitors (Ruxolitinib, additional JAK1/2 and JAK1-selective,baricitinib or INCB39110), Pim kinase inhibitors (e.g., INCB53914), PI3kinase inhibitors including PI3K-delta selective and broad spectrum PI3Kinhibitors (e.g., INCB50465 and INCB54707), PI3K-gamma inhibitors suchas PI3K-gamma selective inhibitors, MEK inhibitors, CSF1R inhibitors,TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, and Mer; e.g.,INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors,Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTOR inhibitors,proteasome inhibitors (Bortezomib, Carfilzomib), HDAC-inhibitors(panobinostat, vorinostat), DNA methyl transferase inhibitors,dexamethasone, bromo and extra terminal family members inhibitors (forexample, bromodomain inhibitors or BET inhibitors, such as INCB54329 orINCB57643), LSD1 inhibitors (e.g., INCB59872 or INCB60003), arginaseinhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors(e.g., epacadostat, NLG919 or BMS-986205), and PARP inhibitors (e.g.,olaparib or rucaparib).

For treating cancer and other proliferative diseases, pemigatinib can beused in combination with chemotherapeutic agents, agonists orantagonists of nuclear receptors, or other anti-proliferative agents.Pemigatinib can also be used in combination with a medical therapy suchas surgery or radiotherapy, e.g., gamma-radiation, neutron beamradiotherapy, electron beam radiotherapy, proton therapy, brachytherapy,and systemic radioactive isotopes. Examples of suitable chemotherapeuticagents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, baricitinib, bendamustine, bevacizumab, bexarotene,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,niraparib, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate,panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexeddisodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,rasburicase, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin,sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide,testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene,tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin,vinblastine, vincristine, vinorelbine, vorinostat, veliparib,talazoparib and zoledronate.

In some embodiments, pemigatinib can be used in combination with immunecheckpoint inhibitors. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD27, CD28, CD40,CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma,TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4,BTLA, CTLA-4, LAG3 (e.g., INCAGN2385), TIM3 (e.g., INCB2390), VISTA,PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpointmolecule is a stimulatory checkpoint molecule selected from CD27, CD28,CD40, ICOS, OX40 (e.g., INCAGN1949), GITR (e.g., INCAGN1876) and CD137.In some embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compoundsprovided herein can be used in combination with one or more agentsselected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671, US20170174679, US 20170320875, US 20170342060, US 20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,ipilumimab or AMP-224. In some embodiments, the anti-PD-1 monoclonalantibody is nivolumab or pembrolizumab. In some embodiments, theanti-PD1 antibody is nivolumab. In some embodiments, the anti-PD1antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonalantibody is MGA012. In some embodiments, the anti-PD1 antibody isSHR-1210. Other anti-cancer agent(s) include antibody therapeutics suchas 4-1BB (e.g. urelumab, utomilumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In someembodiments, the PD-L1 inhibitor is INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, pemigatinib can be used in combination with one ormore agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withpemigatinib can comprise nucleoside and nucleotide reverse transcriptaseinhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs), protease inhibitors and other antiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with pemigatinib for thetreatment of cancer include chemotherapeutic agents, targeted cancertherapies, immunotherapies or radiation therapy. Pemigatinib may beeffective in combination with anti-hormonal agents for treatment ofbreast cancer and other tumors. Suitable examples are anti-estrogenagents including but not limited to tamoxifen and toremifene, aromataseinhibitors including but not limited to letrozole, anastrozole, andexemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g.megastrol acetate), and estrogen receptor antagonists (e.g.fulvestrant). Suitable anti-hormone agents used for treatment ofprostate and other cancers may also be combined with pemigatinib. Theseinclude anti-androgens including but not limited to flutamide,bicalutamide, and nilutamide, luteinizing hormone-releasing hormone(LHRH) analogs including leuprolide, goserelin, triptorelin, andhistrelin, LHRH antagonists (e.g. degarelix), androgen receptor blockers(e.g. enzalutamide) and agents that inhibit androgen production (e.g.abiraterone).

Pemigatinib may be combined with or in sequence with other agentsagainst membrane receptor kinases especially for patients who havedeveloped primary or acquired resistance to the targeted therapy. Thesetherapeutic agents include inhibitors or antibodies against EGFR, Her2,VEGFR, c-Met, Ret, IGFR1, or Flt-3 and against cancer-associated fusionprotein kinases such as Bcr-Abl and EML4-Alk. Inhibitors against EGFRinclude gefitinib and erlotinib, and inhibitors against EGFR/Her2include but are not limited to dacomitinib, afatinib, lapitinib andneratinib. Antibodies against the EGFR include but are not limited tocetuximab, panitumumab and necitumumab. Inhibitors of c-Met may be usedin combination with FGFR inhibitors. These include onartumzumab,tivantnib, and INC-280. Agents against Abl (or Bcr-Abl) includeimatinib, dasatinib, nilotinib, and ponatinib and those against Alk (orEML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with pemigatinibinclude inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of theRaf-MAPK pathway, inhibitors of JAK-STAT pathway, and inhibitors ofprotein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with pemigatinib. In some embodiments, the JAK inhibitor isselective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with pemigatinib includechemotherapy combinations such as platinum-based doublets used in lungcancer and other solid tumors (cisplatin or carboplatin plusgemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with pemigatinib include:dacarbazine (DTIC), optionally, along with other chemotherapy drugs suchas carmustine (BCNU) and cisplatin; the “Dartmouth regimen,” whichconsists of DTIC, BCNU, cisplatin and tamoxifen; a combination ofcisplatin, vinblastine, and DTIC; or temozolomide. Pemigatinib may alsobe combined with immunotherapy drugs, including cytokines such asinterferon alpha, interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, pemigatinib as described herein can beadministered in the form of pharmaceutical compositions which refers toa combination of pemigatinib as described herein, and at least onepharmaceutically acceptable carrier. These compositions can be preparedin a manner well known in the pharmaceutical art, and can beadministered by a variety of routes, depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration may be topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, oral or parenteral. Methods for ocular delivery can includetopical administration (eye drops), subconjunctival, periocular orintravitreal injection or introduction by balloon catheter or ophthalmicinserts surgically placed in the conjunctival sac. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal, or intramuscular injection or infusion; orintracranial, e.g., intrathecal or intraventricular, administration.Parenteral administration can be in the form of a single bolus dose, ormay be, for example, by a continuous perfusion pump. Pharmaceuticalcompositions and formulations for topical administration may includetransdermal patches, ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like may benecessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, pemigatinib in combination with one or morepharmaceutically acceptable carriers. In making the compositionsdescribed herein, the active ingredient is typically mixed with anexcipient, diluted by an excipient or enclosed within such a carrier inthe form of, for example, a capsule, sachet, paper, or other container.When the excipient serves as a diluent, it can be a solid, semi-solid,or liquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, suppositories, sterileinjectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 4 to about 5 mg, or about 4.5 mg, of the activeingredient. In some embodiments, the unit dosage form contains about 9mg of the active ingredient. In some embodiments, the unity dosage formcontains about 13.5 mg of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture ofpemigatinib. When referring to these pre-formulation compositions ashomogeneous, the active ingredient is typically dispersed evenlythroughout the composition so that the composition can be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid pre-formulation is then subdivided intounit dosage forms of the type described above containing from, forexample, 0.1 to about 500 mg of the active ingredient of the presentdisclosure.

In some embodiments, pemigatinib is administered orally. In someembodiments, pemigatinib is administered once daily. In someembodiments, pemigatinib is administered in a daily dose of about 5 mgto about 20 mg. In some embodiments, pemigatinib is administered in adaily dose of about 10 mg to about 15 mg. In some embodiments,pemigatinib is administered in a daily dose of about 13.5 mg. In someembodiments, pemigatinib is administered as a tablet. In someembodiments, the tablet comprises about 0.5 mg to about 10 mg ofpemigatinib. In some embodiments, the tablet comprises about 0.5 mg toabout 5 mg pemigatinib. In some embodiments, the tablet comprises about2 mg, about 4.5 mg, about 9 mg, about 13.5 mg, or about 18 mg ofpemigatinib. In some embodiments, the tablet comprises about 0.5 mg ofpemigatinib. In some embodiments, the tablet comprises about 2 mg ofpemigatinib. In some embodiments, the tablet comprises about 4.5 mg ofpemigatinib. In some embodiments, the tablet comprises about 9 mg ofpemigatinib. In some embodiments, the tablet comprises about 13.5 mg ofpemigatinib. In some embodiments, the tablet comprises about 18 mg ofpemigatinib.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the pemigatinib, or compositions as describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of pemigatinib can vary according to, forexample, the particular use for which the treatment is made, the mannerof administration of the compound, the health and condition of thepatient, and the judgment of the prescribing physician. The proportionor concentration of pemigatinib in a pharmaceutical composition can varydepending upon a number of factors including dosage, chemicalcharacteristics (e.g., hydrophobicity), and the route of administration.For example, pemigatinib can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

Pemigatinib can also be formulated in combination with one or moreadditional active ingredients which can include any pharmaceutical agentsuch as anti-viral agents, vaccines, antibodies, immune enhancers,immune suppressants, anti-inflammatory agents and the like.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment of cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of pemigatinib, or any of the embodiments thereof. Suchkits can further include one or more of various conventionalpharmaceutical kit components, such as, e.g., containers with one ormore pharmaceutically acceptable carriers, additional containers, etc.,as will be readily apparent to those skilled in the art. In someembodiments, the kit further comprises a CYP3A4 inhibitor. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

EXAMPLES Example 1. Synthesis of Pemigatinib Step 1:4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS#958230-19-8, Lakestar Tech, Lot: 124-132-29: 3.0 g, 17 mmol) andethylamine (10M in water, 8.3 mL, 83 mmol) in 2-methoxyethanol (20 mL,200 mmol) was heated to 130° C. and stirred overnight. The mixture wascooled to room temperature then concentrated under reduced pressure. Theresidue was treated with 1N HCl (30 mL) and stirred at room temperaturefor 1 h then neutralized with saturated NaHCO₃ aqueous solution. Theprecipitate was collected via filtration then washed with water anddried to provide the desired product (2.9 g, 92%). LC-MS calculated forC₁₀H₁₂N₃O [M+H]⁺ m/z: 190.1; found: 190.1.

Step 2:5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol) and[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid(Aldrich, cat #21360: 2 g, 7 mmol) in xylenes (250 mL) was heated toreflux with azeotropic removal of water using Dean-Stark for 2 days atwhich time LC-MS showed the reaction was complete. The mixture wascooled to room temperature and the solvent was removed under reducedpressure. The residue was dissolved in tetrahydrofuran (500 mL) and then2.0 M lithium tetrahydroaluminate in THF (37 mL, 74 mmol) was addedslowly and the resulting mixture was stirred at 50° C. for 3 h thencooled to room temperature. The reaction was quenched by addition ofwater, 15% aqueous NaOH and water. The mixture was filtered and washedwith THF. The filtrate was concentrated and the residue was washed withCH₂Cl₂ and then filtered to get the pure product (11 g, 82%). LC-MScalculated for C₁₈H₂₁F₂N₄O₂[M+H]⁺ m/z: 363.2; found: 363.1.

Step 3:3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A solution of triphosgene (5.5 g, 18 mmol) in tetrahydrofuran (30 mL)was added slowly to a mixture of5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine(5.6 g, 15 mmol) in tetrahydrofuran (100 mL) at 0° C. and then themixture was stirred at room temperature for 6 h. The mixture was cooledto 0° C. and then 1.0 M sodium hydroxide in water (100 mL, 100 mmol) wasadded slowly. The reaction mixture was stirred at room temperatureovernight and the formed precipitate was collected via filtration,washed with water, and then dried to provide the first batch of thepurified desired product. The organic layer in the filtrate wasseparated and the aqueous layer was extracted with methylene chloride.The combined organic layer was concentrated and the residue wastriturated with methylene chloride then filtered and dried to provideanother batch of the product (total 5.5 g, 92%). LC-MS calculated forC₁₉H₁₉F₂N₄O₃[M+H]⁺ m/z: 389.1; found: 389.1.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. wasadded sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). Theresulting mixture was stirred at 0° C. for 30 min then benzenesulfonylchloride (0.444 mL, 3.48 mmol) was added. The reaction mixture wasstirred at 0° C. for 1.5 h at which time LC-MS showed the reactioncompleted to the desired product. The reaction was quenched withsaturated NH₄Cl solution and diluted with water. The white precipitatewas collected via filtration then washed with water and hexanes, driedto afford the desired product (1.2 g, 98%) as a white solid which wasused in the next step without further purification. LC-MS calculated forC₂₅H₂₃F₂N₄O₅S [M+H]⁺ m/z: 529.1; found: 529.1.

Step 5:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran(80 mL) at −78° C. was added freshly prepared lithium diisopropylamide(1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixturewas stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18mmol) was added slowly. The reaction mixture was stirred at −78° C. for30 min then quenched with water and extracted with EtOAc. The organicextracts were combined then washed with water and brine. The organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography eluted with 0 to 20% EtOAc in DCM to give thedesired product as a white solid (1.68 g, 91%). LC-MS calculated forC₂₆H₂₃F₂N₄O₆S (M+H)⁺ m/z: 557.1; found: 556.9.

Step 6:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) indichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol),followed by acetic acid (2 mL, 30 mmol). The resulting yellow solutionwas stirred at room temperature overnight then sodiumtriacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture wasstirred at room temperature for 3 h at which time LC-MS showed thereaction went to completion to the desired product. The reaction wasquenched with saturated NaHCO₃ then extracted with ethyl acetate(EtOAc). The organic extracts were combined then washed with water andbrine. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by flash chromatography eluted with 0 to 40% EtOAcin DCM to give the desired product as a yellow solid (1.85 g, 95%).LC-MS calculated for C₃₀H₃₂F₂N₅O₆S (M+H)⁺ m/z: 628.2; found: 628.0.

Step 7:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (pemigatinib)

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran(40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2mmol). The resulting solution was stirred at 50° C. for 1.5 h thencooled to room temperature and quenched with water. The mixture wasextracted with dichloromethane (DCM) and the organic extracts werecombined then washed with water and brine. The organic layer was driedover Na₂SO₄ and concentrated. The residue was purified by flashchromatography eluted with 0 to 10% MeOH in DCM to give the desiredproduct as a white solid, which was further purified by prep HPLC (pH=2,acetonitrile/H₂O). LC-MS calculated for C₂₄H₂₈F₂N₅O₄ (M+H)⁺ m/z: 488.2;found: 488.0. ¹H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05(t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q,J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br,2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).

Example A. Study to Assess the Effect of Itraconazole and Rifampin onPemigatinib Pharmacokinetics when Administered Orally in HealthyPatients

This Example describes an ongoing Phase 1 clinical study to assess theeffect of multiple doses of itraconazole, a potent CYP3A4 inhibitor, orrifampin, a potent CYP3A4 inducer, on the single-dose pharmacokinetics(e.g., C_(max), AUC_(0-t) and AUC_(0-∞)) of pemigatinib.

In addition, this study also evaluates the safety and tolerability ofpemigatinib when administered alone or in combination with itraconazoleor rifampin. Safety and tolerability is assessed by monitoring adverseevents, vital signs, physical examinations, 12-lead ECGs, and clinicallaboratory blood and urine sample assessments. Pharmacokinetic endpointsinclude t_(max), AUC_(0-t), AUC_(0-∞), t_(1/2), CL/F, and V_(z)/F.

The study is an open-label, fixed sequence, drug-drug interaction (DDI)study to assess the effect of multiple doses of itraconazole or rifampinon the single-dose PK of pemigatinib. Thirty-six healthy participantsare divided into 2 cohorts of 18 participants. The study enrolls healthyadult participants aged 18 to 55 years.

In the first cohort, Cohort 1, participants receive each of thefollowing treatments in succession:

-   -   Day 1: pemigatinib 4.5 mg (4.5 mg×1) single dose administered        orally in the fasted state;    -   Days 4 through 7: Itraconazole 200 mg (100 mg×2) QD in the fed        state (4 doses);    -   Day 8: pemigatinib 4.5 mg (4.5 mg xl) single dose and        itraconazole 200 mg (100 mg×2) single dose in the fasted state;        and    -   Day 9 through 11: Itraconazole 200 mg (100 mg×2) single dose in        the fed state.

Vital signs (oral temperature; respiratory rate; automated, seated bloodpressure; and pulse) are obtained at screening, check-in, and follow-up;at 0 hour (predose) on Days 1 and 8; and at approximately 1, 2, 3, 6,and 24 hours after the morning dose on Day 4 and Day 9. Clinical safetylaboratory assessments are performed at screening; on Days −1, 2, 5, 9,10, and 11; and at follow-up. A serum pregnancy is obtained at screeningand follow-up. A urine pregnancy test is obtained at check-in for eachvisit for all women. On Day 8, a 12-lead ECG is performed predose, 2hours postdose, and approximately 24 hours postdose. On other days,12-lead ECGs are performed only at predose.

Pemigatinib is administered as follows: Participants enter the CRU onDay −1 and remain in the clinic until discharged on Day 12. They receivea single oral dose of pemigatinib 4.5 mg under fasted conditions onDay 1. On Days 4 through 7, they receive itraconazole 200 mg QD underfed conditions. On Day 8, participants receive single doses ofpemigatinib 4.5 mg and itraconazole 200 mg under fasted conditions. OnDays 9 through 11, participants will receive itraconazole 200 mg QD doseunder fed conditions. Participants are discharged from the unit on Day12.

In the second cohort, Cohort 2, participants receive each of thefollowing treatments in succession:

-   -   Day 1: pemigatinib 13.5 mg (4.5 mg×3) single dose administered        orally in the fasted state;    -   Days 4 through 10: Rifampin 600 mg (300 mg×2) QD in the fasted        state (7 doses);    -   Day 11: pemigatinib 13.5 mg (4.5 mg×3) single dose and rifampin        600 mg (300 mg×2) single dose in the fasted state;    -   Day 12: Rifampin 600 mg (300 mg×2) QD in the fasted state.

Vital signs (oral temperature; respiratory rate; automated, seated bloodpressure; and pulse) are obtained at screening, check-in and follow-up;at 0 hour (predose) on Days 1 and 11; and at approximately 1, 2, 3, 6,and 24 hours after the morning dose on Days 4, 10, and 12. Clinicalsafety laboratory assessments are performed at screening; on Days −1, 2,8, and 13; and at follow-up. A serum pregnancy test is obtained atscreening and follow-up. A urine pregnancy test is obtained at check-infor each visit for all women. On Day 11, a 12-lead ECG is performedpredose, 2 hours postdose, and approximately 24 hours postdose. On otherdays, 12-lead ECGs is performed only at predose.

Pemigatinib is administered as follows: Participants enter the CRU onDay −1 and remain in the clinic until discharged on Day 13. They receivea single oral dose of pemigatinib 13.5 mg under fasted conditions onDay 1. On Days 4 through 10, they will receive rifampin 600 mg QD underfasted conditions. On Day 11, participants receive single doses ofpemigatinib 13.5 mg and rifampin 600 mg under fasted conditions. On Day12, participants receive rifampin 600 mg QD under fasted conditions.Participants are discharged from the unit on Day 12. Blood samples forPK analysis are collected at 0 hour (predose) and at 0.5, 1, 2, 3, 4, 6,8, 12, and 16 hours postdose on Day 1; at 24 hours postdose on Day 2; at48 hours postdose on Day 3; at 72 hours postdose on Day 4; at 0 hour(predose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose on Day11; at 24 hours postdose on Day 12; and at 48 hours postdose on Day 13.

In both cohorts, each participant undergoes a screening period, atreatment period, and a post-treatment period. During the screeningperiod (up to 28 days), participants sign an informed consent form andare assessed for eligibility. In the treatment period, PK blood samplesare collected at scheduled times after each pemigatinib administrationto determine plasma concentrations of pemigatinib. The post-treatmentperiod will include a follow-up visit 30+3 days after the final dose ofpemigatinib.

Screening lasts up to 28 days. The planned length of treatment is 12days for Cohort 1 and 13 days for Cohort 2. Follow-up is 30+3 days afterthe last dose of the study drug. Total duration is up to 66+3 days forCohort 1 and 69+3 days for Cohort 2.

The key inclusion criteria is male or female healthy adult participantsaged 18 to 55 years, with a body mass index between 18 and 32 kg/m²inclusive. In addition, the participants should exhibit no clinicallysignificant findings on screening evaluations (e.g., no current orrecent history of a clinically significant bacterial, fungal, parasitic,mycobacterial, or viral infection, and not receiving systemicantibiotics). The participants must be willing to avoid pregnancy orfathering children.

The key exclusion criteria include the following:

-   -   History or clinical manifestations of significant metabolic,        hepatic, renal (eGFR≤90 mL/min/1.73 m2), hematological,        pulmonary, cardiovascular, GI, urological, neurological, or        psychiatric disorders;    -   History of clinically significant corneal and retinal disorders;    -   History of a calcium/phosphate homeostasis disorder and/or        extensive ectopic mineralization/calcification;    -   Serum calcium and phosphorus outside of the institutional normal        range;    -   Current or recent history (<30 days before screening) of a        clinically significant bacterial, fungal, parasitic, or        mycobacterial infection, or currently receiving systemic        antibiotics. Current clinically significant viral infection at        screening or check-in;    -   Clinically meaningful findings on screening assessments        (clinical, laboratory, and ECG);    -   Inability or unwillingness to comply with study procedures;    -   History of malignancy, with the exception of cured basal cell or        squamous cell carcinoma of the skin;    -   History or presence of an abnormal ECG before dose        administration that, in the investigator's opinion, is        clinically significant (QTcF interval >450 milliseconds);    -   Resting pulse <45 bpm or >100 bpm, confirmed by repeat testing        at screening;    -   History of unstable ischemic heart disease or uncontrolled        hypertension (blood pressure >140/90 mm Hg at screening,        confirmed by repeat testing);    -   History of stomach, cholecystectomy, or intestinal surgery,        except that appendectomy will be allowed;    -   Presence of a malabsorption syndrome possibly affecting drug        absorption (eg, Crohn's disease or chronic pancreatitis);    -   Use of any tobacco-containing or nicotine-containing products        (including cigarette, pipe, cigar, chewing tobacco, nicotine        patch, or nicotine gum) within 1-month of screening;    -   Hemoglobin, white blood cell, or platelet count below the lower        reference limit of the testing laboratory at screening or        check-in, confirmed by repeat testing. Absolute neutrophil count        <laboratory lower limit of normal at screening or check-in,        confirmed by repeat testing;    -   Hepatic transaminases (ALT and AST), alkaline phosphatase, or        total bilirubin (except volunteers with Gilbert's disease, for        which total bilirubin must be ≤2.0×ULN) >1.25 above the        laboratory-defined ULN at screening or check-in, confirmed by        repeat testing;    -   Evidence of hepatitis B virus or hepatitis C virus infection or        risk of reactivation or HIV: positive result for hepatitis B        surface antigen, hepatitis B core antibody, hepatitis C        antibody, or positive HIV antibody screening tests;    -   Current treatment or treatment within 30 days or 5 half-lives        (whichever is longer) before the first dose of study medication        with another investigational medication or current enrollment in        another investigational drug protocol;    -   Use of any medications (including prescription and        over-the-counter) or nonprescription preparations (including        vitamins, minerals, and phytotherapeutic/herbal/plant-derived        preparations) within 7 days before study entry, unless deemed        acceptable by the investigator;    -   Any condition that would, in the investigator's judgment,        interfere with full participation in the study, including        administration of study drug and attending required study        visits, pose a significant risk to the participant, or interfere        with interpretation of study data; and    -   Known hypersensitivity or severe reaction to pemigatinib or        excipients of pemigatinib.

In Cohort 1, pemigatinib is administered orally as a tablet with a unitdose strength of 4.5 mg and a dosage level of 4.5 mg. Itraconazole isadministered orally as a capsule with a unit dose strength of 100 mg anda dosage level of 200 mg.

In Cohort 2, pemigatinib is administered orally as a tablet with a unitdosage strength of 4.5 mg and a dosage level of 13.5 mg. Rifampin isadministered orally as a capsule with a unit dose strength of 300 mg anda dosage level of 600 mg.

Plasma concentrations of pemigatinib are quantified by LC-MS.Pemigatinib was assayed with a linear range of 1 nM to 1000 nM. PKparameters of pemigatinib are derived by non-compartmental analysis. Thelog-transformed PK parameters are compared by treatment using ANOVA. Thegeometric mean ratios and two-sided 90% confidence intervals of C_(max),AUC0-t, and AUC_(0-∞) for pemigatinib are calculated by ANOVA.

Preliminary Results

Of the 36 volunteers enrolled (cohort 1, n=18; cohort 2, n=18), allcompleted the study. Demographics and baseline characteristics are shownbelow in Table 3.

TABLE 3 Patient Demographics and Baseline Characteristics Clinical Trial(n = 36) Characteristic Cohort 1 (n = 18) Cohort 2 (n = 18) Median(range) age, y 34.5 (24-50) 30 (19-49) Women, n (%) 8 (44) 11 (61) Race,n (%) White 15 (83) 13 (72) Black 1 (6) 4 (22) Asian 0 0 AmericanIndian/Alaska Native 0 1 (6) Other 2 (11) 0 Mean (SD) weight, kg 74.2(11.2) 73.5 (15.8) 2 Mean (SD) body mass index, 26.8 (3.1) 26.4 (4.0)kg/m²

FIG. 1 shows the PK of pemigatinib in healthy volunteers afteradministration of pemigatinib with or without coadministration ofitraconazole. Pemigatinib was absorbed quickly with or withoutitraconazole coadministration (median T_(max)=2.0 h in each case).Pemigatinib plasma concentrations subsequently declined in a biphasicmanner. The estimated geometric mean t_(1/2) was significantly shorterfor pemigatinib alone versus pemigatinib coadministered withitraconazole (11.8 vs. 18.8 h, respectively; P<0.0001). The C_(max) andAUC_(0-∞) of pemigatinib increased by 17% and 88%, respectively, uponcoadministration with itraconazole; both increases were significant(P<0.0001).

FIG. 2 shows the PK of pemigatinib in healthy volunteers afteradministration of pemigatinib with or without coadministration ofrifampin. Pemigatinib was absorbed quickly with or without rifampincoadministration (median T_(max)=1.5 h vs. 1.0 h for pemigatinib withvs. without rifampin coadministration, respectively). Pemigatinib plasmaconcentrations subsequently declined in a biphasic manner. The estimatedgeometric mean t_(1/2) was significantly longer for pemigatinib aloneversus pemigatinib coadministered with rifampin (12.7 vs. 4.7 h,respectively; P<0.0001). The C_(max) and AUC₀, of pemigatinib decreasedby 62% and 88%, respectively, upon coadministration with rifampin; bothdecreases were significant (P<0.0001).

Table 4 shows the PK parameters of Cohort 1 and Cohort 2.

TABLE 4 PK parameters PK Parameters AUC_(0-t), AUC_(0-∞), C_(max), nMT_(max), h t_(1/2), h nM · h nM · h CL/F, L/h Vz/F, L Cohort 1Pemigatinib 60.1 ± 25.3 2.00 12.1 ± 2.74  674 ± 246  712 ± 252 14.5 ±4.55 244 ± 75.8 alone (n = 18) 55.2 (1.00, 4.00) 11.8 634 672 13.7 233Pemigatinib + 68.2 ± 22.1 2.00 19.2 ± 4.30 1270 ± 381 1320 ± 397 7.63 ±2.34 206 ± 63.2 itraconazole 64.7 (1.00, 3.00) 18.8 1210 1270 7.29 198(n = 18) P value 0.0098  0.262 <0.0001 <0.0001 <0.0001 <0.0001 0.0001Geometric mean 117 — — 191 188 — — ratio,* % (107-129) (177-206)(175-203) (90% CI) Cohort 2 Pemigatinib  187 ± 63.3 1.50 12.9 ± 2.901980 ± 526 2040 ± 556 14.8 ± 4.86 267 ± 73.1 alone (n = 18) 176 (0.50,3.00) 12.7 1900 1960 14.1 258 Pemigatinib + 69.7 ± 20.0 1.00 5.05 ± 2.76  289 ± 74.9   301 ± 75.5 97.5 ± 23.8 673 ± 259 rifampin 66.9 (1.00,3.00) 4.69 280 292 94.7 640 (n = 18) P value <0.0001  0.141 <0.0001<0.0001 <0.0001 <0.0001 <0.0001 Geometric mean 38.0 — — 14.7 14.9 — —ratio,* % (33.2-43.5) (13.7-15.8) (13.9-16.1) (90% CI) Values arepresented in the format of “Mean ± SD and Geometric Mean except thatT_(max) is reported as median (range)Safety and Tolerability

Treatment-emergent adverse events (TEAEs) were reported n 7 (39%)volunteers in Cohort 1 and 6 (33%) volunteers in Cohort 2 with headachereported as the most common TEAE in both cohorts. There were no TEAEs ofgrade 3 or high, no treatment discontinuations or dose interruptions dueto TEAEs, and no serious TEAEs or deaths.

A safety summary of the study is provided in Table 5.

TABLE 5 Safety Summary TEAE, n (%) Cohort 1 Cohort 2 (n = 18) (n = 18)Any TEAE 7 (38.9) 6 (33.3) Headache 3 (16.7) 4 (22.2) Nausea 1 (5.6) 3(16.7) Rash papular 2 (11.1) 1 (5.6) Somnolence 2 (11.1) 1 (5.6) Drymouth 2 (11.1) 0 (0) Dry skin 2 (11.1) 0 (0) Paraesthesia 0 (0) 2 (11.1)Vision blurred 2 (11.1) 0 (0)

CONCLUSION

Coadministration of pemigatinib with itraconzole, a potent CYP3A4inhibitor, resulted in a clinically significant increase in pemigatinibexposure. Coadministration of pemigatinib with rifampin, a potent CYP3A4inducer, resulted in a clinically significant decrease in pemigatinibexposure. Based on these results, it is recommended that the dose ofpemigatinib be reduced by approximately 50% when a strong CYP3A4inhibitor is coadministered, and that coadministration of pemigatinibwith a strong CYP3A4 inducer should be avoided.

Pemigatinib, when administered alone or in combination with itraconazoleor rifampin, was safe and generally well tolerated in this group ofhealthy male and female volunteers.

Example B. In Vitro Metabolism of Pemigatinib by Individual RecombinantHuman Cytochrome P450 Isozymes

In vitro metabolism studies were conducted to determine the humancytochrome P450 (CYP) isozyme(s) capable of metabolizing pemigatinib.Experiments using individual recombinant human CYPs showed thatpemigatinib was predominantly metabolized by CYP3A4. In agreement,experiments using human liver microsomes and selective chemicalinhibitors of CYPs showed the metabolism of pemigatinib was onlyinhibited by ketoconazole, a potent CYP3A4 inhibitor. The in vitrometabolism of pemigatinib by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,and CYP2D6 was negligible. Thus, it is concluded that pemigatinib ispredominately metabolized by CYP3A4.

Pemigatinib was incubated with human liver microsomes in the absence andpresence of selective chemical inhibitors of CYP1A2, CYP2B6, CYP2C8,CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Pemigatinib (1 μM) was incubated(N=3) with human liver microsomes (1 mg/mL of protein), NADPH (2 mM),and 100 mM potassium phosphate buffer (pH 7.4) at 37° C. Parallelincubations using the same conditions included either furafylline (10μM), ticlopidine (2 M), quercetin (10 μM), sulfaphenazole (10 μM),tranylcypromine (20 μM), quinidine (1 μM), or ketoconazole (1 μM) toselectively inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, andCYP3A, respectively (Walsky and Obach 2004, Walsky et al 2006, Khojastehet al 2011). Aliquots were taken at 0, 10, 20, and 30 minutes anddenatured with methanol. After centrifugation to remove the denaturedproteins, the resulting supernatants were analyzed by LC/MS.

To measure pemigatinib levels from in vitro incubations, samples wereinjected onto an Agilent Zorbax 5 μm SB-C18 column (2.1×50 mm) coupledto a ThermoFinnigan LCQ Fleet Ion-Trap mass spectrometer (Thermo-FisherScientific, Waltham, Mass.) operated in positive ionization mode. Themass spectrometer was coupled to a Shimadzu Sil HT-C combinedautosampler/controller combined with a Shimadzu LC-10A binary gradientpump system (Shimadzu Scientific Instruments, Columbia, Md.). Thechromatographic separation was achieved using a gradient elutionconsisting of mobile phase A: 5 mM ammonium formate in deionized water(Millipore Inc., Billerica, Mass.) that had been pH adjusted to pH 3.4with formic acid (approximately 0.1%), and mobile phase B: 100% methanol(recombinant isozyme study) or 100% acetonitrile (chemical inhibitorstudy).

In vitro metabolism studies were conducted to determine the individualhuman recombinant CYP isozymes capable of metabolizing pemigatinib (1μM) and included CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, orCYP3A4. The percent of pemigatinib remaining after a 30-minuteincubation with individual CYPs is shown in Table 6. Of the CYP isozymesevaluated, pemigatinib was metabolized to the greatest extent by CYP3A4.The metabolism of pemigatinib by CYP1A2, CYP2B6, CYP2C8, CYP2C9,CYP2C19, and CYP2D6, was negligible.

TABLE 6 The In Vitro Metabolism of Pemigatinib by Individual HumanRecombinant CYP Isozymes Average Percent (N = 2) of CYP IsozymePemigatinib Remaining vs Control (30 mins) CYP1A2 92 CYP2B6 96 CYP2C8 94CYP2C9 88 CYP2C19 95 CYP2D6 94 CYP3A4 14

To determine the relative contributions of CYP isozymes to themetabolism of pemigatinib in the liver, this compound was incubated intriplicate with human liver microsomes and selective chemical inhibitorsof CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

When pemigatinib was incubated with human liver microsomes in theabsence of chemical inhibitors, 72% of parent remained after 30 minutes,but when co-incubated with ketoconazole (2 M), a selective inhibitor ofCYP3A4, the metabolism of pemigatinib was inhibited (97% of the parentcompound remained). Other selective inhibitors had marginal effects onthe metabolism of pemigatinib; therefore these data are supportive ofthe conclusion that pemigatinib is predominantly metabolized by CYP3A4.

TABLE 7 Effects of Chemical Inhibitors on the Matebolism of Pemigatinibin Human Liver Microsomes. Mean Percent of Pemigatinib RemainingChemical Concentration Inhibitor After 30-Minute Inhibitor (μM) ofIsozyme Incubation (N = 3) Pemigatinib (1 μM) No Inhibitor 72 ± 1Furafylline 10 CYP1A2 67 ± 1 Ticlopidine 2 CYP2B6 67 ± 3 Quercetin 10CYP2C8 77 ± 1 Sulfaphenazole 10 CYP2C9 70 ± 3 Tranylcypromine 20 CYP2C1973 ± 2 Quinidine 1 CYP2D6 71 ± 1 Ketoconazole 2 CYP3A4 97 ± 2

Example C. Model Development for Pemigatinib and Evaluation of Drug-DrugInteractions

A minimal physiologically based pharmacokinetic (PBPK) with advanceddissolution absorption and metabolism (ADAM) absorption model forpemigatinib that incorporates CYP3A4-mediated metabolism derived from invitro data, mass balance data, and clinical PK data (Example A) wasdeveloped. Data from in vitro studies have indicated that CYP3A4 is themajor isozyme responsible for the metabolism of pemigatinib (Example B).Based on mass balance and metabolite identification data, the oralabsorption of pemigatinib is nearly complete and renal excretion is low(˜1.0%), and liver metabolism is inferred to be the major clearancepathway for pemigatinib.

PBPK models that have been validated with clinical pharmacokinetic andDDI data can be used to predict other unknown DDI scenarios. Thesimulation results can also be used to support dose adjustment and labelstatements. The aims of this modeling and simulation study were todevelop a PBPK model for pemigatinib, using in silico, in vitro, andclinical data to predict the drug-drug interaction.

Model Development

The initial PBPK model for pemigatinib was built using in vitro and insilico data. Data from in vitro studies (Example B) have indicated thatCYP3A4 is the major isozyme responsible for the metabolism ofpemigatinib. Based on mass balance and metabolite identification data,the oral absorption of pemigatinib is nearly complete (1.3% of theadministered radioactive dose was recovered as unchanged pemigatinib infeces) and renal excreation is low (˜1.0% of the dose is excreted inurine as unchanged pemigatinib), and liver metabolism is inferred to bethe major clearance pathway for pemigatinib. Therefore, a minimal PBPKwith ADAM absorption model for pemigatinib that incorporatesCYP3A4-mediated metabolism derived from in vitro data and human ADMEdata was then further developed and model was used to describe theclinical PK data from pemigatinib alone cohorts in Example A. Thesensitivity analysis of pemigatinib f_(mCYP3 A4) on drug interactionwith itraconazole suggested that CYP3A4 contributes˜55% of the metabolicclearance for pemigatinib. The verified pemigatinib model was then usedto simulate the observed effect of itraconazole on pemigatibpharmacokinetics, and to confirm the contribution of CYP3A4(f_(mCYP3 A4)) to pemigatinib metabolic clearance. Finally, thepemigatinib PBPK model was applied to simulate the effect of otherinhibitors and inducers on pemigatinib pharmacokinetics.

Simulations were performed using pemigatinib PBPK model and comparedwith the observations in the clinical studies available. The pemigatinibPBPK model was validated by simulation of DDIs between pemigatinib anditraconazole or rifampin using a Simcyp virtual population, with thestudy design matching the corresponding clinical DDI study in healthyvolunteers. The itraconazole capsule (200 mg) was administered dailyfrom Day 1 to Day 6 and a single 4.5-mg dose of pemigatinib tablet wasadministered orally with itraconazole on Day 5. The rifampin capsule(600 mg) was administered daily from Day 1 to Day 8 and a single 13.5-mgdose of pemigatinib tablet was administered orally with rifampin on Day8. The simulations were performed using an age range of 18-55 years(proportion of female volunteers: 0.5).

The verified Pemigatinib PBPK model was used to predict the effect ofother strong (clarithromycin), moderate (diltiazem, erythromycin, andcyclosporine), and mild (fluvoxamine) CYP3A4 inhibitors and moderate(efavirenz) and mild (dexamethasone) CYP3A4 inducers on pemigatinib PK.The Simcyp default PBPK models for clarithromycin, erythromycin,diltiazem, cyclosporine, fluvoxamine, and efavirenz were used in thesesimulations. Dexamethasone PBPK models are not available in the Simcypmodel library. Therefore, a literature reported dexamethasone PBPK modelwas used for simulation. For CYP3A4-mediated inhibition/inductionsimulation, the inhibitors/inducers were administered daily from Day 1to Day 12 and a single 13.5-mg dose of pemigatinib tablet wasadministered orally on Day 8. The simulations were performed using anage range of 18-55 years (proportion of female volunteers: 0.5).

Results

A minimal PBPK with ADAM absorption model for pemigatinib thatincorporates CYP3A4-mediated metabolism derived from in vitro data andin vivo clinical data was developed. FIG. 3 shows the observed andsimulated mean plasma concentration-time profiles for pemigatinibfollowing a single oral dose of 4.5 mg (FIG. 3A) and 13.5 (FIG. 3B) mgpemigatinib tablet alone. Predicted and observed geometric mean plasmaC_(max) and AUC_(0-∞) values for pemigatinib tablets are shown in Table8. The simulated profiles of pemigatinib are comparable to the clinicaldata and the predicted geometric mean C_(max) and AUC_(0-∞) values arewithin 0.93- to 1.11-fold of the observed data.

TABLE 8 Predicted and Observed Exposures (Geometric Mean) Following aSingle Oral Dose of 4.5 mg or 13.5 mg Pemigatinib Tablets PredictedObserved C_(max) AUC Predicted Observed AUC AUC (pred/ (pred/ DoseC_(max) (nM) C_(max) (nM) (h * nM) (h * nM) obs) obs)  4.5 mg 52.6 55.2627 672 0.95 0.93 13.5 mg 176 158 1878 I960 111 0.95

The pemigatinib PBPK model was developed from healthy volunteer was usedto describe cancer patients PK data from phase I dose escalation anddose expansion study (6-20 mg). The model was used to predictpemigatinib plasma concentration-time curves in cancer patients aftermultiple oral dose of 6, 9, 13.5 and 20 mg pemigatinib because only onepatient was dosed for 1, 2 and 4 mg, respectively. FIG. 4 shows theobserved (circles) and simulated (lines) mean plasma concentration-timeprofiles for pemigatinib following a multiple oral dose administration.Predicted and observed geometric mean plasma C_(max) and AUC values forpemigatinib tablets are shown in Table 9. The simulated PK profiles ofpemigatinib are comparable to the clinical data and the predictedgeometric mean C_(max) and AUC values are within 0.676- to 1.18-fold ofthe observed data.

TABLE 9 Predicted and Observed Exposures (Geometric Mean) Following aMultiple Dose of Pemigatinib Tablets Predicted Observed Predicted Cmax,ss Cmax, ss AUCss Observed Cmax, ss AUCss Dose (nM) (nM) (h * nM) AUCss(h * nM) (pred/obs) (pred/obs) 6 mg 77.4 101 1002 1110 0.766 0.902 9 mg116 161 1259 1508 0.720 0.834 13.5 mg 193 175 3073 2600 1.10 1.18 20 mg257 380 3345 4180 0.676 0.800

The sensitivity analysis of pemigatinib f_(mCYP3 A4) on drug interactionwith itraconazole were used to determine CYP3A4 contribution ofmetabolic clearance for pemigatinib. The input of CYP3A4 CL_(int) wasvaried to obtain a range of f_(mCYP3A) from 0.25 to 0.95 (using theSimcyp retrograde calculator). The simulations ofitraconazole-pemigatinib DDIs with different f_(mCYP3A) values forpemigatinib were compared with the observed DDI data. When f_(mCYP3 A4)was assigned to be 55%, the best prediction was achieved by PBPK modelfor the effect of DDI between pemigatinib and itraconazole (FIG. 5 andTable 10).

TABLE 10 Simulated Pemigatinib Geometric Mean C_(max) and AUC Ratiosusing PBPK Model with Various f_(mCYP3A4) Values C_(max) Ratio AUC Ratiof_(mCYP3A4) (%) Predicted Observed Predicted Observed 25 1.09 1.17 1.311.88 55 1.22 1.98 75 1.32 2.88 95 1.44 5.02

The comparison between simulated and observed pemigatinib PK in thepresence and absence of itaconazole or rifampin are presented in FIG. 6and FIG. 7 , respectively. The predicted and observed geometric meanplasma C_(max) and AUC values for pemigatinib tablets are shown in Table11.

TABLE 11 Predicted and Observed Pemigatinib C_(max) and AUC RatiosFollowing a Single Oral Dose of Pemigatinib Tablets With and WithoutItraconazole or Rifampin Administration CYP3A4 C_(max) Ratio AUC RatioPerpetrator Predicted Observed Predicted Observed Itraconazole 1.22(1.20, 1.24) 1.17 (1.07, 1.29) 1.98 (1.91, 2.05) 1.88 (1.75, 2.03)Rifampin 0.604 (0.572, 0.638) 0.380 (0.332, 0.425) 0.323 (0.299, 0.349)0.149 (0.139, 0.161) Values are presented in the format of geometricmean (90% confidence intervals)

The model-predicted pemigatinib AUC ratio of 1.98 (90% CI:1.91, 2.05)and C_(max) ratio of 1.22 (90% CI:1.20, 1.24) are similar to theobserved AUC ratio of 1.88 (90% CI:1.75, 2.03) and C_(max) ratio of 1.17(90% CI:1.07, 1.29) for itraconazole DDI. The predicted geometric meanAUC ratios and C_(max) ratios are within the 90% CI of the observeddata.

However, underprediction is observed for rifampin DDI. Model-predictedpemigatinib AUC ratio of 0.323 (90% CI:0.299, 0.349) and C_(max) ratioof 0.604 (90% CI:0.572, 0.638) are approximately 1.5 to 2-fold highercomparing to the observed AUC ratio of 0.149 (90% CI:0.139, 0.161) andC_(max) ratio of 0.380 (90% CI:0.332, 0.425) for rifampin DDI. InExample A, the observation of an 85% reduction in AUC and 63% decreasein half-life of pemigatinib following rifampin coadministration. Inaddition, the first pass gut and liver metabolism is expected to be lowdue to high permeability and low oral clearance of pemigatinib. All ofthese suggest that a decrease in bioavailability of pemigatinib occurredwith rifampin coadministration, in addition to an increase in systemicclearance (eg, reduced absorption).

The final pemigatinib PBPK model was not able to accurately predictdrug-drug interaction between pemigatinib and rifampin which could bedue to additional DDI effect on absorption of pemigatinib. The modelwith 55% f_(mCYP3 A4) was used to predict DDI effect on pemigatinib PKwhen co-administration with moderate and mild CYP3A4 inducers. Resultsof the simulated effect of strong, moderate, and mild CYP3Ainhibitors/inducers on pemigatinib pharmacokinetics are summarized inTable 12 and illustrated in FIG. 8 .

TABLE 12 Simulated Pemigatinib Drug-Drug Interactions With VariousCYP3A4 Inhibitors or Inducers CYP3A4 Perpetrators Inhibition/Inductionand Dose Regimen Mechanism AUC Ratio C_(max) Ratio Itraconazole 200 mgQD Strong, reversible 1.98 (1.91, 2.05) 1.22 (1.20, 1.24) inhibitionClarithromycin 500 mg Strong, time 1.89 (1.80, 1.98) 1.20 (1.18, 1.21)BID dependent inhibition Erythromycin 500 mg BID Moderate, time 1.66(1.59, 1.73) 1.16 (1.14, 1.17) dependent inhibition Diltiazem 60 mg TIDModerate, time 1.51 (1.46, 1.56) 1.13 (1.12, 1.14) dependent inhibitionFluvoxamine 50 mg QD Mild, reversible inhibition 1.082 (1.075, 1.089)1.048 (1.044, 1.053) Rifampin 600 mg QD Strong, inducer 0.323 (0.299,0.349) 0.604 (0.572, 0.638) Efavirenz 600 mg QD Moderate, inducer 0.482(0.455, 0.512) 0.758 (0.736, 0.781) Dexamethasone 8 mg QD Mild, inducer0.995 (0.994, 0.996) 0.996 (0.996, 0.997) Values are presented in theformat of geometric mean (90% confidence intervals).

The simulated DDI results for co-administration with various CYP3A4inhibitors or inducers were used for pemigatinib dose recommendation.The model-simulated pemigatinib geometric mean C_(max) and AUC ratiosare 1.20 and 1.89, 1.16 and 1.66, 1.13 and 1.51, 1.05 and 1.08, 0.758and 0.482, and 1.00 and 1.00, respectively, when coadministration withstrong inhibitors clarithromycin, moderate inhibitors erythromycin anddiltiazem, a mild inhibitor fluvoxamine, a moderate inducer efavirenzand a mild inducer dexamethasone. The recommendation based on thissimulation and clinical DDI result is to reduce pemigatinib dose byapproximately 50% for coadministration with strong CYP3A4 inhibitors.For coadministration with moderate CYP3A4 inhibitors, themodel-simulated pemigatinib AUCs are increased by approximately 50% andit is covered by safety margin. Therefore, no dose adjustment isrequired with coadministration of pemigatinib and moderate and mildCYP3A4 inhibitors. The simulation and clinical DDI result also suggestthat co-administration of a strong and moderate CYP3A4 inducers shouldbe avoided due to larger than 50% of pemigatinib AUC decrease and nodose adjustment is required with coadministration of pemigatinib andmild CYP3A4 inducers. with clinical data. The estimated f_(mCYP3 A4)(55%) for pemigatinib was verified using the observed clinical DDI studywith itraconazole.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises administering a therapeutically effective amount ofpemigatinib to the patient while avoiding the concomitant administrationof a CYP3A4 perpetrator.
 2. A method of treating cancer comprisingadministering a therapy to a patient in need thereof, wherein thetherapy comprises administering a therapeutically effective amount ofpemigatinib to the patient while avoiding the concomitant administrationof a strong CYP3A4 inhibitor.
 3. The method of claim 1, A method oftreating cancer comprising administering a therapy to a patient in needthereof, wherein the therapy comprises administering a therapeuticallyeffective amount of pemigatinib to the patient while avoiding theconcomitant administration of a moderate to strong CYP3A4 inducer.
 4. Amethod of treating cancer comprising administering a therapy to apatient in need thereof, wherein the therapy comprises administering atherapeutically effective amount of pemigatinib to the patient whileavoiding the concomitant administration of itraconazole.
 5. A method oftreating cancer comprising administering a therapy to a patient in needthereof, wherein the therapy comprises administering a therapeuticallyeffective amount of pemigatinib to the patient while avoiding theconcomitant administration of rifampin.
 6. The method of claim 1,wherein the cancer is bladder cancer, breast cancer, cervical cancer,cancer of the small intestine, colorectal cancer, endometrial cancer,gastric cancer, head and neck cancer, kidney cancer, liver cancer, lungcancer, ovarian cancer, prostate cancer, testicular cancer, uterinecancer, vulvar cancer, esophageal cancer, gall bladder cancer,pancreatic cancer, thyroid cancer, skin cancer, brain cancer, leukemia,multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia,B-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin'slymphoma, Waldenstrom's Macroglubulinemia, myeloproliferative neoplasms,chronic myelogenic lymphoma, acute lymphoblastic lymphoma, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, rhabdosarcoma,lymphosarcoma, osteosarcoma, solid tumor, cholangiocellular carcinoma,and myeloid/lymphoid neoplasms.
 7. The method of claim 6, wherein themyeloid/lymphoid neoplasm is 8p11 myeloproliferative syndrome.
 8. Themethod of claim 6, wherein the cancer is cholangiocellular carcinoma. 9.The method of claim 6, wherein the cancer is bladder cancer.
 10. Themethod of claim 1, wherein the administration of pemigatinib comprises:(a) a continuous daily administration of an intended amount or adjustedamount of pemigatinib to the patient in need thereof; or (b) a 21-daydosing cycle comprising:14 days of daily administration of an intendedamount or adjusted amount of pemigatinib to the patient in need thereofand 7 days without administration of pemigatinib.
 11. The method ofclaim 1, wherein the cancer is liver cancer.